Fatty acid peroxides play a critical role in the aggregation and disaggregation of platelets and hence in thrombosis. Arachidonic acid (AA) is metabolized to a number of hydroperoxides by platelet lipoxygenase and to prostaglandin endoperoxides (PGG2 and PGH2) by cycloxygenase. Cyclic peroxides (CP) synthesized in this laboratory inhibit platelet aggregation and promote disaggregation of AA-aggregated platelets. To determine the mechanism by which simple chemically synthesized CP promote this action, the steps in the metabolism of AA to PGG2, thromboxane A2, PGs and PGI2 in human and rabbit and pig arterial walls will be studied. The effects of CP on platelet c-AMP and c-GMP levels will be examined. Specific structural modification of the CP will be made to study the effects of structure on activity. Hydroperoxides of known stucture will be synthesized and tested as inhibitors of PGI2 synthetase and for their activity on platelet cycloxygenase, thromboxane synthetase and contraction of smooth muscle preparations. These studies will use synthetic CP and hydroperoxides which are uniquely available to us to probe the requirements for these compounds to interact with potential control mechanisms in platelet aggregation. These studies may lead to new compounds of potential use as drugs regulating thrombosis.